2-hydroxypropionic acid derivative and its manufacturing method

ABSTRACT

This invention relates to a novel 2-hydroxypropionic acid derivative and its manufacturing method. Based on its mechanism to inhibit the CPT I, 2-hydroxypropionic acid derivative of this invention has blood glucose lowering effects so that the derivative may be effectively used as an antidiabetic agent having remarkable antidiabetic activity and fewer side effects.

This application is the national phase of PCT/RR97/00133, filed Jul. 2,1997.

TECHNICAL FIELD

This invention relates to 2-hydroxypropionic acid derivative expressedby the following formula (1), its manufacturing method and antidiabeticagent containing it. ##STR1## Wherein:

A is one selected from the radicals expressed by the following (i),(ii), (iii), (iv) and (v); ##STR2## R₁ represents a lower alkyl; Xrepresents hydroxy, mesylate, tosylate or bromine.

(wherein R₂ ˜R₁₇ represent independently hydrogen, halogen, alkoxy,lower alkyl, hydroxy, alkenyl, alkynyl, cyano or amino group; n denotes0, 1 or 2).

BACKGROUND OF ART

The diabetic patients tend to suffer from some disorders such asinhibition of glucose uptake, inhibited glycolysis and increasingbeta-oxidation of fatty acid in their peripheral tissues, which causethe use of fat for their body's energy source instead of glucose andlead to some diseases such as hyperglycemia, hyperlipidemia andhyperketonemia.

The beta-oxidation of fat in diabetic patients occurs in a mitochondrialsubstrate. Carnitine palmitoyl transferase I (CPT I) is an enzyme totransport a higher fatty acid from cytoplasm to a mitochondrial losubstrate, and plays an vital role in limiting the beta-oxidation rate.

Therefore, CPT I inhibitors will be utilized as an effectiveantidiabetic agent in that they may inhibit the beta-oxidation of higherfatty acids, increase the availability of glucose and exert thehypoglycemic, hypolipidemic and hypoketonemic effects.

The typical compounds belonging to the above mentioned CPT I inhibitorsinclude palmoxirate, clomoxir(POCA) and etomoxir, and these compoundsare characterized in that all of them have oxirane carboxylic acid intheir most active site.

The inhibitory action of these oxirane carboxylic acid derivativesagainst the CPT I has yet to be elucidated up to now but it has beenassumed that since these derivatives have the stable covalent bonding inthe active sites of CPT I within cytoplasm, their inhibition actionagainst the CPT I may contributed to the treatment of diabetes.Therefore, a possible mode of action is that when some nucleophilicsubstance at the active site of CPT I initiates to attack the epoxidering structure of oxirane carboxylic acid derivatives, the openedepoxide ring forms a new hydroxyl group and at the same time, CPT I andoxirane carboxylic acid derivative is covalently bonded, thus inhibitingthe CPT I activity.

However, the phase II clinical trials of etomoxir had been discontinuedowing to some side effects associated with prolonged administration,such as enlarged heart and toxicity in the liver, but its cause has notbeen explicitly known up to now.

DISCLOSURE OF INVENTION

Based on the mechanism that these oxirane carboxylic acid derivativeshave exerted inhibitory actions against the CPT I, the inventor et al.have extensively studied to develop some promising compounds with bloodglucose lowering effects, thus showing remarkable antidiabeticactivities and less side effects. To this end, the inventor et al. havecome to know that as a result of screening various kinds of derivativeshaving oxirane carboxylic acid positioned at their most active sites,2-hydroxypropionic acid derivative of the formula 1 with opened epoxyring at oxirane structure has proven to have an excellent antidiabeticactivity and less side effects. In consequence, this invention has beencompleted.

An object of this invention is to provide 2-hydroxypropionic acidderivative expressed by the following formula 1. ##STR3## Wherein: A isone selected from the radicals expressed by the following (i), (ii),(iii), (iv) and (v); ##STR4## R₁ represents a lower alkyl; X representshydroxy, mesylate, tosylate or bromine. (wherein; R₂ ˜R₁₇ representindependently hydrogen, halogen, alkoxy, lower alkyl, hydroxy, alkenyl,alkynyl, cyano or amino group; in particular, R₂, R₃, and R₅ arehydrogen; R₄ is hydrogen, chlorine or methoxy group; R₇, R₈ and R₉ arehydrogen or chlorine; R₁₀, R₁₄, R₁₅ and R₁₇ are hydrogen or methylgroup; R₁₁, R₁₂, R₁₃ and R₁₆ are preferably hydrogen; n denotes 0, 1 or2).

Another object of this invention is to provide some compounds expressedby the above mentioned formula 1.

Another object of this invention is also to provide an antidiabeticagent containing some compounds expressed by the above mentioned formula1.

The compound of the formula 1 according to this invention may beprepared by the following reaction scheme 1: ##STR5## a) 1,6-hexanediolof the structural formula 2, a well known substance and startingmaterial, is reacted with methanesulfonyl chloride to furnish1,6-hexyldimesylate alkyl group of the structural formula 3, beingmesylated to both alcohol groups;

b) 1,6-hexyldimesylate alkyl group is reacted with various kinds ofaromatic alcohol derivatives in the presence of sodium hydride tosynthesize the compound of the general formula 4 having an ether linkageand then, the compound, so synthesized, is further reacted withdiethylmalonic acid to furnish the compound of the general formula 5;

c) The compound of the general formula 5 is hydrolyzed using potassiumhydride to give the compound of the general formula 6 and then,Eschenmorser's salt is added to the compound of the general formula 6 tosynthesize the compounds of the general formula 7, alpha,beta-unsaturated ester;

d) The compounds of the general formula 7, so synthesized, aredihydroxylated using osmium tetroxide as a catalyst to give a desiredcompound 1 (X=hydroxy), and under further tosylation and bromination,each desired of compound I having X=tosylate and X=bromine,respectively, may be obtained.

From the above reaction processes (A) and (B), 6-bromo-1-hexaneol and1,6-dibromohexane may be replaced by 1,6-hexanediol, a startingmaterial. Further, tosylation or direct substitution may also bereplaced by mesylation.

From the above reaction processes (C) and (D), mesylation may bereplaced by tosylation, and the process of using tetrabromomethane,triphenylphosphine and dichloromethane may gain the same results.

The compound of the formula 1 according to this invention may be used asan effective antidiabetic agent. The daily effective dose in adult is10-100 mg/kg.

The compound of the formula 1 according to this invention has proven tohave remarkable blood glucose lowering effects, while being safe inLD₅₀.

According to this invention, an antidiabetic agent containing thecompound of the formula 1 as an active ingredient may be administeredvia the following common dosage forms, i.e., tablets, injections,capsules, etc.

This invention relates to a novel 2-hydroxypropionic acid derivative andits manufacturing method. Based on its inhibitory mechanism on the CPTI, 2-hydroxypropionic acid derivative of this invention has bloodglucose lowering effects so that the above derivative may be effectivelyused as an antidiabetic agent having remarkable antidiabetic activityand less side effects.

BEST MODE FOR CARRYING OUT THE INVENTION

This invention is explained in more detail by the following examples,but the claims are not limited to these examples.

EXAMPLE 1 Ethyl-2,3-dihydroxy-2-(6-benzoxy)hexylpropionate

1) In a 500 ml round-bottomed flask, 60% sodium hydride (6.84 g, 170.92mmol) was placed, and the air inside the flask was substituted by argongas. Dry tetrahydrofuran (200 ml) was added dropwise thereto to form asuspension. After chilling the mixture to 0° C., a solution of1,6-hexanediol (20 g, 169.23 mmol) in dry tetrahydrofuran (200 ml) wasslowly added dropwise, and the mixture stirred at room temperature for20 minutes. To the solution, benzylbromide(20.25 ml, 170.25 mmol) wasadded dropwise and stirred at room temperature for 18 hours. Thereaction mixture was concentrated under reduced pressure to removetetrahydrofuran as a solvent, and the residue was diluted with a mixtureof ethyl acetate (400 ml) and water (50 ml). After washing with water(500 ml×2) and saturated brine (500 ml×2), the solution was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified on a column chromatography (eluent:ethyl acetate/n-hexane=1/3) to give 19.47 g of object compound ascolorless oil (yield: 55%).

IR(neat) 3400(alcohol) cm⁻¹ Mass(EI) 208(M⁺ -1) ¹ H NMR(80 MHz,CDCl₃)δ7.43 (s, 5H), 4.53 (s,2H), 3.66 (t, 2H), 3.50 (t, 2H), 1.81-1.20 (m,8H)

2) In a 250 ml round-bottomed flask, 6-benzyloxy-1-hexanol (14.2 g,67.87 mmol) and p-toluenesulfonyl chloride (14.23 g, 74.66 mmol) wereplaced, and the air inside the flask was substituted by argon gas. Drychloroform (120 ml) was added dropwise thereto, and then dry pyridine(16.47 ml) was injected to the mixture. After stirring at roomtemperature for 3 hours, the reaction mixture was concentrated underreduced pressure to remove chloroform, and the residue was diluted withethyl acetate (400 ml). The solution was washed with diluted aqueoushydrochloric acid (20 ml×2), water (30 ml×2) and saturated brine (30ml×2), dried over anhydrous magnesium sulfate and filtered. Afterconcentrating the solution under reduced pressure, the residue waspurified on a column chromatography (eluent: ethylacetate/n-hexane=1/10) to obtain 24 g of the object compound ascolorless oil (yield: 97%).

Mass(EI) 362 (M⁺ -1) ¹ H NMR(400 MHz, CDCl₃) δ7.63(d,2H), 7.15(s,7H),4.33(s,2H), 3.86(t,2H), 3.27(t,2H), 2.29(s,3H), 1.52-1.11(m,8H)

3) In a 250 ml three-necked round-bottomed flask, 60% sodium hydride(2.28 g, 56.94 mmol) was placed, and the air inside the flask wassubstituted by argon gas. Dry tetrahydrofuran (10 ml) was injectedthereto to form a suspension. After chilling the mixture to 0° C., asolution of diethyl malonate (8.72 g, 54.46 mmol) in dry tetrahydrofuran(100 ml) was slowly added dropwise, and the mixture stirred for about 10minutes. To the mixture, a solution of6-benzoxy-1-(4-methylbenzenesulfoxy)hexane (17.99 g, 49.51 mmol) in drytetrahydrofuran (200 ml) was injected. The reaction mixture was heatedunder reflux for 20 hours to complete the reaction. After removingtetrahydrofuran by evaporating under reduced pressure, the residue wasdiluted with a mixture of ethyl acetate (500 ml) and water (50 ml).After washing with water (50 ml×2) and saturated brine (50 ml×2), thesolution was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified on acolumn chromatography (eluent: ethyl acetate/n-hexane=1/20) to give 16 gof object compound as colorless oil (yield: 92%).

IR(neat) 1740(ester carbonyl) cm⁻¹ Mass(EI) 350(M⁺ -1) ¹ HNMR(400MHz,CDCl₃) δ7.32(s,5H), 4.33(s,2H), 4.13(q,4H), 3.84(t,2H), 3.25(t,1H),1.11-1.70(m,16H)

4) In a 250 ml round-bottomed flask, diethyl 6-benzoxyhexyl malonate(15.9 g, 45.25 mmol) and 85% potassium hydroxide (3.2 g, 48.42 mmol)were placed, and ethanol (160 ml) was injected thereto. The mixture wasstirred at room temperature for 24 hours. After concentrating thereaction mixture under reduced pressure to remove ethanol, the residuewas diluted with 70 ml of water. The solution was washed with diethylether, and the aqueous layer was acidified with dilute aqueoushydrochloric acid, and then extracted by using ethyl acetate (400 ml).The organic layer was washed with water (50 ml×2) and saturated brine(50 ml×2), and dried over anhydrous magnesium sulfate. After filteringand concentrating under reduced pressure, crude product (14.6 g) wasobtained as colorless oil (yield: 100%).

IR(cm⁻¹) 1740(ester, carbonyl of carboxylic acid), 3400(OH of carboxylicacid) Mass(EI) 323(M⁺) ¹ HNMR(400 MHz,CDCl₃) δ7.32(s,5H), 4.21(q,2H),3.35(t,1H), 1.26(t,3H), 4.5(s,2H), 3.45(t,2H), 1.90-1.31 (m,10H)

5) In a 50 ml round-bottomed flask, 60% sodium hydroxide (888.72 mg,22.22 mmol) was placed, and the air inside the flask was substituted byargon gas. Dry tetrahydrofuran (10 ml) was added thereto to form asuspension. After chilling the suspension to 0° C., a solution of ethyl6-benzoxyhexylmalonate (3.42 g, 10.58 mmol) in dry tetrahydrofuran (10ml) was slowly added dropwise, and the mixture stirred at roomtemperature for 20 minutes. Eschenmoser salt (2.15 g) was added theretoat a time, and the resultant mixture was heated under reflux for 6hours. After removing tetrahydrofuran by evaporating under reducedpressure, the residue was diluted with a mixture of ethyl acetate (100ml) and water (20 ml). The solution was washed with 7% aqueoushydrochloric acid (10 ml×2), water (10 ml×2), saturated aqueous sodiumbicarbonate solution (10 ml×2), water (10 ml×2) and saturated brine (10ml×2), and dried over anhydrous magnesium sulfate. After filtering andconcentrating the solution under reduced pressure, the residue waspurified on a column chromatography (eluent: ethylacetate/n-hexane=1/15) to give 2.5 g of the object compound as colorlessoil (yield: 81%)

IR(cm⁻¹) 1740(ester carbonyl) Mass(EI) 291 (M⁺) ¹ HNMR(500 MHz,CDCl₃)δ7.32(s,5H), 4.49(s,2H), 3.46(t,2H), 1.63-1.33(m,8H), 6.11(s,1H),4.20(q,2H), 2.27(t,2H), 1.29(t,3H), 5.4 8(s,1H)

6) In a 50 ml round-bottomed flask, 60% aqueous NMO solution 1.31ml(7.55 mmol), and a mixed solution of acetone and water (50 ml,acetone/water=10/1) were placed, and 0.08 M solution of osmium tetroxidein toluene (4.28 ml, 0.343 mmol) was injected there to. The reactionmixture was added to ethyl 2-(6-benzoxy)hexyl-2-enepropionate (2 g, 6.86mmol), and the resultant mixture was stirred at room temperature for 2 hours. After adding sodium bisulfite, the reaction mixture was stirredfor 20 minutes, and extracted with methylene chloride (100 ml). Thesolution was washed with saturated brine (10 ml×2), dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on a column chromatography (eluent: ethylacetate/n-hexane=1/1) to give 2.2 g of the object compound as whitesolid (yield: 98%).

IR (cm-⁻¹) 1740 (esteric carbonyl), 3450 (alcohol) Mass(EI) 325(M⁺) ¹HNMR(400 MHz,CDCl₃) δ7.26-7.34(m,5H), 3.78(d,1H), 1.30(t,3H),4.49(s,2H), 3.58(d,1H), 4.23-4.28(m,2H), 1.34-1.65(m,10H)

7) In a 25 ml round-bottomed flask, ethyl2,3-dihydroxy-2-(6-benzoxy)hexylpropionate (230 mg,, 0.707 mmol) andp-toluenesulfonyl chloride (161.7 mg, 0.848 mmol) were placed, and theair inside the flask was substituted by argon gas. Dry chloroform (3 ml)was added dropwise thereto, and then dry pyridine (0.18 ml) was injectedto the mixture. After stirring at room temperature for 18 hours, thereaction mixture was concentrated under reduced pressure to removechloroform, and the residue was diluted with ethyl acetate (50 ml). Thesolution was washed with diluted aqueous hydrochloric acid (5 ml×2),water (50 ml×2) and saturated brine (50 ml×2), dried over anhydrousmagnesium sulfate and filtered. After concentrating the solution underreduced pressure, the residue was purified on a column chromatography(eluent: ethyl acetate/n-hexane=1/5) to obtain 289 mg of the objectcompound as colorless oil (yield: 85%).

IR (cm-⁻¹) 1740 (esteric carbonyl) Mass(EI) 479(M⁺) ¹ HNMR(400 Hz,CDCl₃) δ7.76(d,2H), 7.33(s,7H), 4.47(s,2H), 4.23-4.20(m,2H), 4.22(d,1H)3.88(d, 1H), 3.42(t,2H), 2.44(s,3H), 1.61-1.31 (m,10H), 1.28(t,3H)

EXAMPLE 2 Ethyl-2,3-dihydroxy-2-[6-(4-methoxybenzoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using4-methoxybenzyl alcohol instead of benzyl alcohol of Example 1-1) toobtain the title compound.

IR(neat) 1740(ester carbonyl), 3450(alcohol)cm⁻¹ MASS(EI) 354(M⁺ -1) ¹ HNMR(80 MHz, CDCl₃) δ7.28(d, 2H), 6.90(d, 2H), 4.42(s, 2H), 4.27(q, 2H),3.81(s, 3H), 1.91-1.07(m, 10H), 1.31(t, 3H)

EXAMPLE 3 Ethyl-2,3-dihydroxy-2-[6-(4-chlorophenoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using4-chlorophenol instead of benzyl alcohol of Example 1-1) to obtain thetitle compound.

IR(neat) 1740(ester carbonyl), 3400(alcohol)cm⁻¹ MASS(EI) 344(M⁺ -1) ¹ HNMR(400 MHz, CDCl₃) δ7.22(d, 2H), 6.81(d, 2H), 4.25-4.17(m, 2H), 3.90(t,2H), 3.03(d, 1H), 2.78(d, 1H), 1.78-1.38(m, 10H), 1.27(t, 3H)

EXAMPLE 4

Ethyl-2,3-dihydroxy-2-[6-(3,5-dimethylpyrazol)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using3,5-dimethylpyrazol-1-methanol instead of benzyl alcohol of Example 1-1)to obtain the title compound.

IR(neat) 1740(ester carbonyl), 3400(alcohol) MASS(EI) 314(M⁺) ¹ H NMR(80MHZ) δ5.73(s,1H) 4.25(q,2H), 3.89(t,2H) 3.61(m,2H) 2.18(s,6H)1.80-1.19(m,10H)

EXAMPLE 5 Ethyl-2,3-dihydroxy-2-[6-(5-methyl-2-furanmethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using5-methyl-2-furan-methanol instead of benzyl alcohol of Example 1-1) toobtain the title compound.

¹ H NMR (300 MHz, CDCl₃) δ6.17(d, 1H), 5.91(d, 1H), 4.36(s, 2H), 3.78(t,1H), 3.59(d, 1H), 3.53(s, 1H), 3.44(t, 2H), 2.29(s, 3H), 2.1(m, 1H),1.7-1.0(m, 10H), 1.31(t, 3H)

EXAMPLE 6 Ethyl-2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using2-thiopenethanol instead of benzyl alcohol of Example 1-1) to obtain thetitle compound.

¹ H NMR (300 MHz, CDCl₃) δ7.14(dd, 1H), 6.93(dd, 1H), 6.85(dd, 1H),4.31(dq--dq, 2H), 3.79(t, 1H), 3.7-3.5(m, 4H), 3.44(t, 2H), 3.09(t, 2H),2.10(m, 1H), 1.7-1.0(m, 9H), 1.32(t, 3H)

EXAMPLE 7 Ethyl-2,3-dihydroxy-2-[6-(5-chloro-2-thiophenmethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using5-chloro-2-thiophenmethanol instead of benzyl alcohol of Example 1-1) toobtain the title compound.

¹ H NMR (300 MHz, CDCl₃) δ6.77(d, 1H), 6.74(d, 1H), 4.53(s, 2H),4.28(dq--dq, 2H), 3.78(m, 1H), 3.59(d, 1H), 3.54(s, 1H), 3.44(t, 2H),2.15(m, 1H), 1.7-1.0(m, 9H), 1.31(t, 3H)

EXAMPLE 8 Ethyl-2,3-dihydroxy-2-[6-(3-chloro-2-thiophenmethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using,3-chloro-2-thiophenmethoxy instead of benzyl alcohol of Example 1-1) toobtain the title compound.

¹ H NMR (300 MHz, CDCl₃) δ7.26(d, 1H), 6.89(d, 1H), 4.63(s, 2H),4.28(dq--dq, 2H), 3.78(t, 1H), 3.59(d, 1H), 3.53(s, 1H), 3.46(t, 2H),2.1(m, 1H), 1.7-1.1(m, 9H), 1.31(t, 3H)

EXAMPLE 9 Ethyl 2-hydroxy-2-bromo-2-[6-(4-chlorophenoxy)hexyl]propionate

In a 25 ml round-bottomed flask, ethyl2,3-dihydroxy-2-[6-(4-chlorophenoxy)hexyl] propionate (105 mg, 0.305mmol) obtained from Example 3 was placed, and the air inside the flaskwas substituted by argon gas. Dry methylene chloride (1 ml) was injectedthereto. To the mixture, a solution of triphenylphosphine (160 mg, 0.61mmol) in dry methylene chloride (2 ml) and that of tetrabromomethane101.2 mg (0.305 mmol) in dry methylene chloride (1.5 ml) were addedsequentially. The resultant mixture was stirred at room temperature for20 hours. After concentrating the reaction solution under reducedpressure, the residue was purified on a column chromatography (eluent:ethyl acetate/n-hexane=1/1) to give 110 mg of the object compound aswhite solid (yield: 89%).

¹ HNMR(400 MHz, CDCl₃) δ7.72(d,2H), 6.80(d,2H), 4.29(q,2H), 3.89(t,2H),3.77(d,1H) 3.58(d,1H), 1.76-1.33(m,10H), 1.28(t,3H)

EXAMPLE 10 Ethyl2-hydroxy-3-(4-methylbenzenesulfoxy)-2-[6-benzoxyhexyl]propionate

In a 25 ml round-bottomed flask, ethyl2,3-dihydroxy-2-[6-(benzoxy)hexyl]propionate (230 mg, 0.707 mmol)prepared from Example 1 and p-toluenesulfonyl chloride (161.7 mg, 0.848mmol) were placed, and the air inside the flask was substituted by argongas. Dry chloroform (3 ml) was added dropwise thereto, and then drypyridine (0.18 ml) was injected to the mixture. After stirring at roomtemperature for 18 hours, the reaction mixture was concentrated underreduced pressure to remove chloroform, and the residue was diluted withethyl acetate (50 ml). The solution was washed with diluted aqueoushydrochloric acid (5 ml×2), water (50 ml×2) and saturated brine (50ml×2), dried over anhydrous magnesium sulfate and filtered. Afterconcentrating the solution under reduced pressure, the residue waspurified on a column chromatography (eluent: ethyl acetate/n-hexane=1/5)to obtain 289 mg of the object compound as colorless oil (yield: 85%).

IR(cm⁻¹) 1740(ester carbonyl) Mass(EI) 479(M⁺) ¹ HNMR(400 MHz,CDCl₃)δ7.76(d,2H), 7.33(s,7H), 4.47(s,2H), 4.23-4.20(m,2H), 4.22(d,1H), 3.88(d, 1H), 3.42(t,2H), 2.44(s,3H), 1.61-1.31 (m, 10H), 1.28(t,3H)

EXAMPLE 11 Ethyl2-hydroxy-3-bromo-2-[6-(2-thiophenethoxy)hexyl]propionate

1) Ethyl-2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate (580 mg,1.7 mmol) prepared from Example 6 was dissolved in dry pyridine 10 ml,and p-toluenesulfonyl chloride (3.31 g, 17 mmol) was added thereto. Themixture was stirred at room temperature for 3 hours. The reactionmixture was diluted by adding ethyl acetate (50 ml), and the resultantsolution was washed with 1N diluted aqueous hydrochloric acid, 5%aqueous sodium bicarbonate solution (40 ml×2), distilled water (40 ml)and saturated brine (20 ml). The solution was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on a column chromatography (eluent: ethylacetate/n-hexane=1/10) to give 770 mg of ethyl2-hydroxy-3-(4-methylbenzenesulfoxy)-2-[6-(2-thiophenmethoxy)hexyl]propionateas pale yellow oil (yield: 88.9%).

¹ H NMR (300 MHz, CDCl₃) δ7.77 (2H, d, J=8.09 Hz, benzene H), 7.34 (2H,d, J=7.95 Hz, benzene H), 7.13 (1H, d, thiophene H₅), 6.92 (1H, m,thiophene H₄), 6.84 (1H, s(br), thiophene H₃), 4.22 (3H, m, CO₂ CH₂ C₃,1H of --CH₂ --OTs), 3.99 (1H, d, J=9.68 Hz, 1H of --CH₂ -OTs), 3.63 (2H,t, J=6.73 Hz, Ar--CH₂ CH₂ O--), 3.42 (2H, t, J=6.41 Hz, ArCH₂ CH₂ O--CH₂--), 3.36 (1H, s, t-OH), 3.08 (2H, t, J=6.62 Hz, Ar--CH₂ CH₂ O--), 2.45(3H, s, tosyl-CH₃), 1.54 (5H, m, aliphatic H), 1.27 (3H, t, CO₂ CH₂ CH₃,4H, m, aliphatic H), 1.08 (1H, m, aliphatic H)

2) Dissolved was ethyl2-hydroxy-3-(4-methylbenzenesulfoxy)-2-[6-(2-thiophenemethoxy)hexyl]propionate (203 mg, 0.4 mmol) in acetone (7 ml), and lithiumbromide (0.36 g, 4.2 mmol) was added thereto. After heating under refluxfor 16 hours, the reaction mixture was concentrated under reducedpressure to remove acetone. The residue was diluted with ethyl acetate(20 ml), and the organic layer was washed with distilled water (20 ml)and saturated brine (10 ml), dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified on a column chromatography (eluent: ethyl acetate/n-hexane=1/5)to give 160 mg of object compound as colorless oil (yield: 96.9%)

¹ H NMR (300 MHz, CDCl₃) δ7.14 (1H, dd, J=5.16 Hz, J=1.07 Hz, thiopheneH.), 6.93 (1H, dd, J=5.03 Hz, J=3.46 Hz, thiophene H₄), 6.84 (1H, m,thiophene H₃), 4.29 (2H, m, CO₂ CH₂ CH₃), 3.67 (1H, d, J=10.28 Hz, 1H of--CH₂ --Br), 3.64 (2H, t, J=6.82 Hz, Ar--CH₂ CH₂ O--), 3.51 (1H, s,t-OH), 3.47 (1H, d, J=10.18 Hz, 1H of --CH₂ --Br), 3.44 (2H, t, J=6.56Hz, ArCH₂ CH₂ O--CH₂ --), 3.09 (2H, t, J=6.80 Hz, Ar--CH₂ CH₂ O--),1.85˜1.45 (4H, m, aliphatic H), 1.4˜1.2 (5H, m, aliphatic H, 3H, t, CO₂CH₂ CH₃), 1.15 (1H, m, aliphatic H) ¹³ C NMR (75 MHz, CDCl₃) δ173.51,141.38, 126.59, 125.0, 123.56, 77.0, 71.35, 70.90, 62.50, 39.72, 37.30,30.45, 29.50, 29.32, 25.88, 23.79, 14.24

EXAMPLE 12 Ethyl2-hydroxy-3-bromo-2-[6-(5-chlorothiophenemethoxy)hexyl]propionate

The object compound was prepared by the same procedures as Example 11but using ethyl2,3-dihydroxy-2-[6-(5-chlorothiophenemethoxy)hexyl]propionate instead ofethyl 2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate.

¹ H NMR (300 MHz, CDCl₃) δ6.77(d, 1H), 6.74(d, 1H), 4.53(s, 2H),4.29(dq--dq, 2H), 3.66(d, 1H), 3.51(s, 1H), 3.47(d, 1H), 3.44(t, 2H),1.85-1.1(m, 10H), 1.33(t, 3H)

¹³ C NMR (75 MHz, CDCl₃) δ

173.48, 140.45, 129.91, 125.52, 125.27, 70.0, 67.54, 62.48, 39.69,37.28,29.42, 29.27, 25.80, 25.82, 23.76, 14.23

EXAMPLE 13 Ethyl2-hydroxy-3-bromo-2-[6-(3-chlorothiophenemethoxy)hexyl]propionate

The object compound was prepared by the same procedures as Example 11but using ethyl2,3-dihydroxy-2-[6-(3-chlorothiophenemethoxy)hexyl]propionate instead ofethyl 2,3-dihydroxy-2-[6-(2-thiophenethoxy) hexyl]propionate.

¹ H NMR (300 MHz, CDCl₃) δ7.26(d, 1H), 6.89(d, 1H), 4.63(s, 2H),4.29(dq--dq, 2H), 3.66(d, 1H), 3.50(s, 1H), 3.48(t, 2H), 3.47(d, 1H),1.85-1.1(m, 10H), 1.32(t, 3H)

¹³ C NMR (75 MHz, CDCl₃) δ

173.49, 134.05, 127.47,124.68,123.45, 70.28, 64.79, 62.48, 39.69, 37.29,29.40, 29.26, 25.7, 25.79, 23.76, 14.23

EXAMPLE 14 Ethyl-2,3-dihydroxy-2-[6-(5-methyl-2-thiophenmethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using5-methyl-2-thiophenmethanol instead of benzyl alcohol of Example 1-1) toobtain the title compound.

¹ H NMR (300 MHz, CDCl₃) δ6.76 (1H, d, J=3.36 Hz, thiophene H₃), 6.60(1H, m, thiophene H₄), 4.55 (2H, s, Ar--CH₂ O--), 4.28 (2H, m, CO₂ CH₂--CH₃), 3.78 (1H, t(br), 1H of --CH₂ --OH), 3.59 (1H, dd, 1H of --CH₂--OH), 3.54 (1H, s, t-OH), 3.43 (2H, t, J=6.52 Hz, ArCH₂ O--CH₂ --),2.46 (3H, sd, J=0.88 Hz, thiophene-CH₃), 2.14 (1H, dd, --CH₂ --OH), 1.58(4H, m, aliphatic H), 1.31 (5H, m, aliphatic H), 1.31 (3H, t, J=7.15 Hz,CO₂ CH₂ CH₃), 1.1 (1H, m, aliphatic H)

EXAMPLE 15Ethyl-2,3-dihydroxy-2-[6-(5-methoxy-2-thiophenmethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using5-methoxy-2-thiophenmethoxy instead of benzyl alcohol of Example 1-1) toobtain the title compound.

¹ H NMR (300 MHz, CDCl₃) δ6.59 (1H, d, J=3.76 Hz, thiophene H₃), 6.03(1H, d, J=3.78 Hz, thiophene H₄), 4.48 (2H, s, Ar--CH₂ O--), 4.28 (2H,m, J=7.15 Hz, CO₂ CH₂ CH₃), 3.87 (3H, s, --OCH₃), 3.78 (1H, t, 1H of--CH₂ --OH), 3.59 (1H, dd, 1H of --CH₂ --OH), 3.52 (1H, s, t-OH), 3.42(2H, t, J=6.53 Hz, ArCH₂ O--CH₂ --), 2.1 (1H, dd, --CH₂ --OH), 1.67 1.31(9H, m, aliphatic H), 1.31 (3H, t, J=7.12 Hz, CO₂ CH₂ CH₃), 1.1 (1H, m,aliphatic H)

EXAMPLE 16Ethyl-2,3-dihydroxy-2-[6-(4-methoxy-2-thiophenmethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using4-methoxy-2-thiophenmethanol instead of benzyl alcohol of Example 1-1)to obtain the title compound.

¹ H NMR (300 MHz, CDCl₃) δ6.65 (1H, s, thiophene H), 6.18 (1H, d, J=1.27Hz, thiophene H), 4.54 (2H, s, Ar--CH₂₀ --), 4.28 (2H, q(br), CO₂ CH₂CH₃), 3.78 (3H, s, --OCH₃), 3.60 (s, t-OH), 3.55 (1H, d, J=8.96 Hz, 1Hof --CH₂ --OH), 3.45 (3H, t, J=6.49 Hz, ArCH₂ O--CH₂ --, 1H of --CH₂--OH), 2.15 (1H, br, --CH₂ --OH), 1.65˜1.1 (10H, m, aliphatic H), 1.31(3H, t, CO₂ CH₂ CH₃)

EXAMPLE 17 Ethyl-2,3-dihydroxy-2-[6-(3-thiophenmethoxy) hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using3-thiophenmethanol instead of benzyl alcohol of Example 1-1) to obtainthe title compound. ¹ H NMR (300 MHz, CDCl₃) δ7.29 (1H, m, thiopheneH₅), 7.20 (1H, s(br), thiophene H₂), 7.07 (1H, d(br), J=4.77 Hz,thiophene H₄), 4.50 (2H, s, Ar--CH₂ O--), 4.28 (2H, q, J=7.11 Hz, CO₂CH₂ CH₃), 3.78 (1H, t, 1H of --CH₂ --OH), 3.59 (1H, d, J=11.20 Hz, 1H of--CH₂ --OH), 3.54 (1H, t-OH), 3.44 (2H, t, J=6.50 Hz, ArCH₂ O--CH₂ --),2.16 (1H, br, --CH₂ --OH), 1.6 (5H, m, aliphatic H), 1.3 (4H, m,aliphatic H), 1.3 (3H, t, J=7.10 Hz, CO₂ CH₂ CH₃)

EXAMPLE 18 Ethyl-2,3-dihydroxy-2-[6-(3-thiophenethoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using3-thiophenethanol instead of benzyl alcohol of Example 1-1) to obtainthe title compound.

¹ H NMR (300 MHz, CDCl₃) δ7.25 (1H, dd, J=4.93 Hz, J=3.03 Hz, thiopheneH₅), 7.02 (1H, m, thiophene H₂), 6.98 (1H, dd, J=4.9 Hz, J=1.13 Hz,thiophene H₄), 4.28 (2H, m, CO₂ CH₂ CH,), 3.77 (1H, m, 1H of --CH₂--OH), 3.62 (2H, t, J=7.03 Hz, Ar--CH₂ CH₂ O--), 3.59 (1H, d, J=11.21Hz, 1H of --CH₂ --OH), 3.55 (1H, s, t-OH), 3.42 (2H, t, J=6.58 Hz, ArCH₂CH₂ O--CH₂ --), 2.91 (2H, t, J=7.0 Hz, Ar--CH₂ CH₂ O--), 2.1 (1H, m,--CH₂ --OH), 1.72˜1.23 (9H, m, aliphatic H), 1.32 (3H, t, J=7.09 Hz, CO₂CH₂ CH₃), 1.09 (1H, m, aliphatic H)

EXAMPLE 19 Ethyl-2,3-dihydroxy-2-[6-(2-thiophenoxy)hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using2(5H)-thiophenone instead of benzyl alcohol of Example 1-1) to obtainthe title compound.

¹ H NMR (300 MHz, CDCl₃) δ6.71 (1H, dd, J=3.76 Hz, J=5.82 Hz, thiopheneH₄), 6.54 (1H, dd, J=5.75 Hz, J=1.43 Hz, thiophene H₅), 6.19 (1H, dd,J=3.75 Hz, J=1.46 Hz, thiophene H₃), 4.29 (2H, dq--dq, J=7.15 Hz, CO₂CH₂ CH₃), 4.01 (2H, t, J=6.42 Hz, ArO--CH₂ --), 3.79 (1H, t(br), 1H ofCH₂ --OH), 3.59 (1H, dd, 1H of --CH₂ --OH), 3.55 (1H, s, t-OH), 2.12(1H, m, CH₂ --OH), 1.80˜1.25 (9H, m, aliphatic H), 1.32 (3H, t, J=7.13Hz, CO₂ CH₂ --CH₃), 1.13 (1H, m, aliphatic H)

EXAMPLE 20 Ethyl-2,3-dihydroxy-2-[6-(2-thiophenmethoxy) hexyl]propionate

The procedures described in Example 1-1)˜1-6) were repeated but using2-thiophenmethanol instead of benzyl alcohol of Example 1-1) to obtainthe title compound.

¹ H NMR (300 MHz, CDCl₃) δ7.28 (1H, dd, J=4.65 Hz, J=1.74 Hz, thiopheneH₅), 6.98˜6.96 (2H, m, thiophene H₃, H₄), 4.65 (2H, s, Ar--CH₂ O--),4.27 (2H, dq--dq, CO₂ CH₂ CH₃, J=7.2 Hz, J_(gem) =14.2 Hz), 3.78 (1H, t,1H of --CH₂ --OH), 3.58 (1H, dd, J_(gem) =11.20 Hz, 1H of --CH₂ --OH),3.55 (1H, s, t-OH, D₂ O exchangeable), 3.46 (2H, t, J=6.6 Hz, ArCH₂O--CH₂ --), 2.19 (1H, dd, --CH₂ --OH, D₂ O exchangeable), 1.7˜1.5 (5H,m, aliphatic H), 1.4-1.2 (4H, m, aliphatic H), 1.31 (3H, t, J=7.17 Hz,CO₂ CH₂ CH₃), 1.1 (1H, m, aliphatic H)

EXAMPLE 21 Ethyl2-hydroxy-3-bromo-2-[6-(4-methoxy-2-thiophenemethoxy)hexyl]propionate

The object compound was prepared by the same procedures as Example 11but using ethyl2,3-dihydroxy-2-[6-(4-methoxy-2-thiophenemethoxy)hexyl]propionateinstead of ethyl 2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate.

¹ H NMR (300 MHz, CDCl₃) δ6.65 (1H, s, thiophene H), 6.17 (1H, s,thiophene H), 4.53 (2H, s, Ar--CH₂ O--), 4.29 (2H, m, CO₂ CH₂ CH₃), 3.78(3H, s, --OCH₃), 3.66 (1H, d, J=10.24 Hz, 1H of --CH₂ --Br), 3.53˜3.42(4H, m, 1H of --CH₂ --Br, ArCH₂ O--CH₂ --, t-OH), 1.85˜1.16 (13H, m,aliphatic H, CO₂ CH₂ CH₃) ¹³ C NMR (75 MHz, CDCl₃) δ

173.45, 157.52, 140.49, 118.27, 96.44, 76.95, 69.95, 67.62, 62.44,57.09, 39.67, 37.26, 29.41, 29.25, 25.78, 23.72, 14.20

EXAMPLE 22 Ethyl 2-hydroxy-3-bromo-2-[6-(3-thiophenemethoxy)hexyl]propionate

The object compound was prepared by the same procedures as Example 11but using ethyl 2,3-dihydroxy-2-[6-(3-thiophenemethoxy)hexyl]propionateinstead of ethyl 2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate.

¹ H NMR (300 MHz, CDCl₃) δ7.30 (1H, dd, J=4.82 Hz, J=3.0 Hz, thiopheneH₅), 7.20 (1H, s(br), thiophene H₂), 7.07 ((H, d, J=4.82 Hz, thiopheneH₄), 4.50 (2H, s, Ar--CH₂ --), 4.29 (2H, m, CO₂ CH₂ CH₃), 3.67 (1H, d,J=10.25 Hz, 1H of --CH₂ --Br), 3.51 (1H, d, J=9.4 Hz, 1H of --CH₂ --Br),3.44 (2H, t, J=6.53 Hz, ArCH₂ O--C₂), 3.46 (1H, s, t-OH), 1.8˜1.5 (5H,m, aliphatic H), 1.33 (3H, t, J=7.11 Hz, CO₂ CH₂ --CH₃), 1.33 (4H, m,aliphatic H), 1. 14 (1H, m, aliphatic H) ¹³ C NMR (75 MHz, CDCl₃)δ173.48, 139.74, 127.26, 125.85, 122.50, 77.0, 70.17, 68.07, 62.47,39.69, 37.29, 29.52, 29.32, 25.89, 23.78, 14.22

EXAMPLE 23 Ethyl2-hydroxy-3-bromo-2-[6-(3-thiophenethoxy)hexyl]propionate

The object compound was prepared by the same procedures as Example 11but using ethyl 2,3-dihydroxy-2-[6-(3-thiophenethoxy)hexyl]propionateinstead of ethyl 2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate.

¹ H NMR (300 MHz, CDCl₃) δ7.25 (1H, dd, J=4.88 Hz, J=2.97 Hz, thiopheneH₅), 7.02 (1H, m, thiophene H₂), 6.98 (1H, dd, J=4.89 Hz, J=1.17 Hz,thiophene H₄), 4.3 (2H, m, CO₂ CH₂ CH₃), 3.67 (1H, d, J=10.25 Hz, 1H of--CH₂ --Br), 3.62 (2H, t, J=7.08 Hz, Ar--CH₂ CH₂ O--), 3.52 (1H, s,t-OH), 3.48 (1H, d, J=10.23 Hz, 1H of --CH₂ --Br), 3.42 (2H, t, J=6.57Hz, ArCH₂ CH₂ O--CH₂ --), 2.94 (2H, t, J=7.01 Hz, Ar--CH₂ CH₂ O--),1.85-1.1 (10H, m, aliphatic H), 1.33 (3H, t, J=7.1 Hz, CO₂ CH₂ CH₃)

EXAMPLE 24 Ethyl 2-hydroxy-3-bromo-2-[6-(2-thiophenemethoxy)hexyl]propionate

The object compound was prepared by the same procedures as Example 11but using ethyl 2,3-dihydroxy-2-[6-(2-thiophenemethoxy)hexyl]propionateinstead of ethyl 2,3-dihydroxy-2-[6-(2-thiophenethoxy)hexyl]propionate.

¹ H NMR (300 MHz, CDCl₃) δ7.28 (1H, s(br), thiophene H₅), 6.96 (2H, m,thiophene H₃, H₄), 4.64 (2H, s, Ar--CH₂ O--), 4.28 (2H, m, CO₂ CH₂ CH₃),3.66 (1H, d, J=10.24 Hz, 1H of --CH₂ --Br), 3.54 (1H, s(br), t-OH), 3.46(1H, d, J=10.01 Hz, 1H of --CH₂ --Br), 3.45(2H, t, J=6.36 Hz, ArCH₂O--CH₂ --), 1.83˜1.5 (5H, m, aliphatic H), 1.4˜1.2 (4H, m, aliphatic H),1.32 (3H, t, J=7.1 Hz, CO₂ CH₂ CH₃), 1.16 (1H, m, aliphatic H) ¹³ C NMR(75 MHz, CDCl₃) δ

173.38, 141.34, 126.46, 126.01, 125.49, 76.89, 69.82, 67.19, 62.37,39.64, 37.21, 29.37, 29.20, 25.75, 23.67, 14.15

EXPERIMENTAL EXAMPLE 1 Blood Glucose Lowering Effects of the CompoundsPrepared by the Procedures of Example 1-13

Two groups of male diabetes-induced Sprague-Dawley rats (each of 4-5rats weighing about 250 g per group) were used for this experiment. 45mg/kg of streptozotocin (STZ) dissolved in 0.1M citrate buffer (pH 4.5,0-4° C.) was injected to the tail vein of fasted rats for 1 day. Afterelapse of 7 days, their blood glucose concentration were measured andanimals having the blood serum concentration of more than 350 mg/dl wereused as diabetes-induced rats for this experiment. The rats wereintravenously administered at a daily dose of 1 ml/kg, while the normalcontrol group received equal volume of 0.1M citrate buffer.

7 days after being treated with streptozotocin, diabetes-induced ratswere orally administered at a dose of 50 mg/kg of the compounds preparedby the procedures of Examples 1-13. Then, at time intervals of 90 mins,120 mins and 180 mins, their blood glucose concentrations were measuredand the smallest values were taken. The compounds of Example 1-13 weredissolved in 30% ethanol until its final concentration became 2 ml/kg,while the control group was orally received equal volume of 30% ethanol.

Significant difference between two groups was determined by ANOVA test,together with a post hoc test using Newman-Keuls test.

The test results was shown in the following table 1.

                  TABLE 1                                                         ______________________________________                                        Blood glucose lowering effects of the Examples 1-13                                 Compound  Blood glucose lowering rate %                                 ______________________________________                                        Example 1   38.5                                                                Example 2 10.0                                                                Example 3 23.0                                                                Example 4 19.8                                                                Example 5 22.0                                                                Example 6 1.2                                                                 Example 7 19.2                                                                Example 8 26.0                                                                Example 9 22.0                                                                Example 10 34.1                                                               Example 11 13.0                                                               Example 12 26.4                                                               Example 13 19.3                                                             ______________________________________                                    

As noted in the above table 1, the compounds of this invention haveproven to have remarkable blood glucose lowering effects ondiabetes-induced rats.

EXPERIMENTAL EXAMPLE 2 Toxicity test

The acute toxicity tests on rats were performed using the compoundprepared by the procedure of the Example 1. Mature rats weighing 200-250g were orally given the compound of the Example 1 dissolved inethylacetate in parallel with its gradually increasing concentration.Then, LD₅₀ was calculated by number of killed animals. LD₅₀ was 481.5mg/kg.

We claim:
 1. A compound of the following formula 1 or a pharmaceuticallyacceptable salt thereof; ##STR6## Wherein: A is one selected from theradicals expressed by the following (i), (ii), (iii), (iv) and (v);##STR7## R₁ represents a lower alkyl; X represents hydroxy, mesylate,tosylate or bromine.(wherein R₂ ˜R₁₇ represent independently hydrogen,halogen, alkoxy, lower alkyl, hydroxy, alkenyl, alkynyl, cyano or aminogroup; n denotes 0, 1 or 2).
 2. A compound of the formula 1 or apharmaceutically acceptable salt thereof according to claim 1, wherein:Ais one expressed by the following radical (i); ##STR8## R₂ R₃ and R₅ arehydrogen; R₄ is hydrogen, chlorine or methoxy group.
 3. A compound ofthe formula I or a pharmaceutically acceptable salt thereof according toclaim 1, wherein:A is one expressed by the following radical (ii);##STR9## R₇, R₈ and R₉ are hydrogen or chlorine.
 4. A compound of theformula 1 or a pharmaceutically acceptable salt thereof according toclaim 1, wherein:A is one expressed by the following radical (iii);##STR10## R₁₀ is hydrogen or methyl group; R₁₁ and R₁₂ are hydrogen. 5.A compound of the formula 1 or a pharmaceutically acceptable saltthereof according to claim 1, wherein:A is one expressed by thefollowing radical (iv); ##STR11## R₁₃ is hydrogen; R₁₄ is hydrogen ormethyl group.
 6. A compound of the formula I or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein:A is one expressedby the following radical (v); ##STR12## R₁₅ and R₁₇ are hydrogen ormethyl group; R₁₆ is hydrogen.
 7. A process for manufacturing theCompound of the formula I according to claim 1, wherein:a)1,6-hexanediol of the structural formula 2, a well known substance andstarting material, is reacted with methanesulfonyl chloride to furnish1,6-hexyldimesylate alkyl group of the structural formula 3, beingmesylated to both alcohol groups; b) 1,6-hexyldimesylate alkyl group isreacted with various kinds of aromatic alcohol derivatives in thepresence of sodium hydride to synthesize the compound of the generalformula 4 having an ether linkage and then, the compound, sosynthesized, is further reacted with diethylmalonic acid to furnish thecompound of the general formula 5; c) The compound of the generalformula 5 is hydrolyzed using potassium hydride to give the compound ofthe general formula 6 and then, Eschenmorser's salt is added to thecompound of the general formula 6 to synthesize the compounds of thegeneral formula 7, alpha, beta-unsaturated ester; d) The compounds ofthe general formula 7, so synthesized, are dihydroxylated using osmiumtetroxide as a catalyst to give a desired compound 1 (X=hydroxy), andunder further tosylation and bromination, each desired of compound Ihaving X=tosylate and X=bromine, respectively, may be obtained.##STR13## .
 8. An antidiabetic agent containing the compound or apharmaceutically acceptable salt thereof expressed by the formula 1according to claim 1.